The goal of the proposed research is develop new chemical methodologies to enable the synthesis of bioactive flavonoid and xanthone-derived natural products that could lead to novel, anti-cancer and anti-infective agents. Chemical methodologies that will be developed include novel [4+2] dehydrogenative cycloadditions for the synthesis of prenylflavonoid and related Diels-Alder natural products, enantioselective [4+2] cycloadditions of 2'-hydroxychalcones and dienes using chiral boron complexes, metal-catalyzed, asymmetric rearrangement of 3-alloxyflavones, vinylogous addition of siloxyfurans to 5-hydroxychromones to synthesize tetrahydroxanthones, and photocycloaddition of m-quinone methide (m-QM) intermediates to construct bicyclo[3.2.2] ring systems. Professor Porco and colleagues will apply these new methodologies to the chemical synthesis of bioactive natural product targets including kuwanons G and H, sangennol F, sangennon C, sorocenol B, secalonic acids A and D, microsphaerin B, and acremoxanthone A. Collaborations are in place to evaluate compounds in biological assays, including their efficacy as human gastrin-releasing peptide receptor (GRP-R) antagonists, as inhibitors of the E3 ubiquitin ligase gp78, and against geographic isolates of the malarial parasite P. falciparum. The aims of the proposed project are to: Achieve total syntheses of the GRP-R antagonists kuwanons G and H and the asymmetric syntheses of sorocenol B, sanggenol F, and sanggenons A and C. Develop asymmetric syntheses of the tetrahydroxanthones blennolides A and B and accomplish total syntheses of the dimeric natural products secalonic acids A and D and microsphaerin B. Achieve syntheses of the anti-infective agents acremodinin A and acremoxanthone A. The proposed project will enable new research directions for Professor Porco and his collaborators involving the use of nanoparticles in organic reactions, asymmetric catalysis, and novel cycloaddition strategies that are not possible with current grant programs.